{"gene":"TRIM38","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2014,"finding":"TRIM38 constitutively interacts with TAB2 and TAB3 and promotes their lysosome-dependent degradation independent of its E3 ubiquitin ligase activity, thereby negatively regulating TNFα- and IL-1β-triggered NF-κB activation","method":"Co-immunoprecipitation, overexpression/knockdown/knockout with NF-κB reporter assays, lysosome inhibitor rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KO with defined phenotype, lysosome-dependent mechanism confirmed by multiple orthogonal approaches including TAB2 translocation assay","pmids":["24434549"],"is_preprint":false},{"year":2015,"finding":"TRIM38 catalyzes K48-linked polyubiquitination of the TLR3/4 adaptor TRIF at K228 and promotes its proteasomal degradation, negatively regulating TLR3/4-mediated type I IFN and proinflammatory cytokine induction; additionally, TRIM38 induced by type I IFNs mediates lysosomal degradation of TAB2 to suppress TNFα/IL-1β signaling in IFN-primed immune cells","method":"Ubiquitination assays with site-specific mutagenesis (K228), proteasome inhibitor rescue, Trim38 knockout mice challenged with polyI:C/LPS/Salmonella","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination assay with mutagenesis, KO mouse model with in vivo phenotype, two orthogonal mechanisms demonstrated","pmids":["26392463"],"is_preprint":false},{"year":2012,"finding":"TRIM38 targets the TLR3 adaptor TRIF for K48-linked polyubiquitination and proteasomal degradation; the PRYSPRY domain of TRIM38 interacts with the N-terminus of TRIF, and the RING/B-box domain is required for ubiquitination activity","method":"Co-immunoprecipitation, domain mapping, ubiquitination assays, MG132 rescue, overexpression/knockdown reporter assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and ubiquitination assay in single lab, consistent with independent replication in PMID:26392463","pmids":["23056470"],"is_preprint":false},{"year":2011,"finding":"TRIM38 functions as an E3 ubiquitin ligase, promoting both K48- and K63-linked polyubiquitination of cellular proteins and self-ubiquitination; an intact RING domain is required for these activities; TRIM38 localizes to the cytoplasm; enterovirus 71 infection induces TRIM38 degradation","method":"Ubiquitination assays with RING domain mutants, immunofluorescence localization, viral infection experiments","journal":"Virology journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro ubiquitination assay with domain mutagenesis, direct localization by immunofluorescence, single lab","pmids":["21306652"],"is_preprint":false},{"year":2017,"finding":"NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes, acting as a docking scaffold to promote TAB2/3 lysosomal degradation and suppress NF-κB activation","method":"Co-immunoprecipitation, overexpression studies in RA-FLS, NF-κB activity assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP demonstrating three-way interaction, single lab, consistent with prior TRIM38-TAB2/3 mechanism","pmids":["28295271"],"is_preprint":false},{"year":2018,"finding":"TRIM38 promotes lysosome-dependent degradation of TAB2 in osteoclast precursor cells, suppressing RANKL-induced NF-κB activation and inhibiting osteoclast differentiation; conversely, TRIM38 promotes osteoblast differentiation via NF-κB suppression","method":"Overexpression/knockdown in osteoclast and osteoblast precursors, NF-κB reporter assays, lysosome-dependent degradation assays","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined cellular phenotype, mechanistic link to TAB2 degradation, single lab","pmids":["29753717"],"is_preprint":false},{"year":2021,"finding":"TRIM38 interacts with GLUT1 and promotes its ubiquitination and degradation, thereby restricting glycolytic capacity and tumor progression in bladder cancer cells","method":"TAP/MS substrate identification, co-immunoprecipitation, ubiquitination assay, loss-of-function proliferation/migration assays, xenograft model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based substrate identification followed by Co-IP and functional rescue, single lab","pmids":["34906161"],"is_preprint":false},{"year":2023,"finding":"TRIM38 binds CCT6A and promotes its K48-linked ubiquitination and degradation at K127/K138 residues; loss of CCT6A degradation elevates c-Myc protein levels and activates the MYC pathway in colorectal cancer","method":"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis, KO/KD functional assays, AOM/DSS tumorigenesis model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ubiquitination with lysine mutagenesis, Co-IP, in vivo model, single lab","pmids":["40047371"],"is_preprint":false},{"year":2023,"finding":"TRIM38 mediates K48-linked ubiquitination of MITA (STING) promoting its degradation; this ubiquitination is higher in M2 macrophages, keeping MITA expression low and inhibiting pyroptosis, thereby maintaining immune tolerance at the maternal-fetal interface","method":"Co-immunoprecipitation, ubiquitination assays, macrophage polarization experiments (M1/M2), functional pyroptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitination assay, mechanistic link to pyroptosis in defined cell context, single lab","pmids":["38012139"],"is_preprint":false},{"year":2024,"finding":"TRIM38, induced by IFN-I during RSV infection, downregulates RIG-I by K48-linked ubiquitination and promotes RIG-I degradation; TRIM38 competes with TRIM25 for binding to the RIG-I N-terminus (aa 25–43 region), preventing TRIM25-mediated K63 ubiquitination and activation of RIG-I, thereby attenuating IFN-I production as a negative feedback mechanism","method":"Co-immunoprecipitation with domain mapping, ubiquitination assays, overexpression competition experiments, RSV infection model","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with defined binding region mapping, ubiquitination assay, competition experiment, single lab","pmids":["38630167"],"is_preprint":false},{"year":2025,"finding":"TRIM38 interacts with Zika virus NS3 protein via its RING domain and promotes NS3 degradation through a lysosome-dependent mechanism utilizing its E3 ligase activity; RING domain deletion abrogates NS3 interaction and impairs antiviral activity; TRIM38 also upregulates the RIG-I/MDA5 pathway and IFN-β early during ZIKV infection","method":"Co-immunoprecipitation, RING domain deletion mutants, lysosome inhibitor rescue, overexpression/knockout in U251 cells, IFN-β reporter assays","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mutants and lysosome inhibitor rescue, KO confirmed with opposite phenotype, single lab","pmids":["40006954"],"is_preprint":false},{"year":2022,"finding":"TRIM38 promotes TRAF6 degradation, leading to inactivation of the TAK1/NF-κB signaling pathway and protection of H9c2 cardiomyoblasts from hypoxia/reoxygenation injury; TAK1 inhibition rescues the H/R injury exacerbated by TRIM38 deficiency","method":"Adenoviral overexpression/knockdown, western blotting, TAK1 inhibitor (5Z-7-oxozeaenol) rescue experiments","journal":"PeerJ","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological rescue and western blotting only; TRAF6 ubiquitination not directly demonstrated in this paper","pmids":["36061751"],"is_preprint":false},{"year":2024,"finding":"TRIM38 mediates K48-linked polyubiquitination of TRAF6 and promotes its proteasomal degradation in response to RANKL, thereby inhibiting NFATc1 activity and osteoclastogenesis; TRIM38 binds TRAF6 directly","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown of TRIM38, TRAP staining, bone resorption assay, OVX mouse model","journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and in vivo rescue model, single lab","pmids":["39033726"],"is_preprint":false},{"year":2025,"finding":"TRIM38 binds p53 and promotes its ubiquitination-proteasomal degradation; MEHP (a DEHP metabolite) inhibits TRIM38-mediated ubiquitination of p53, leading to p53 accumulation, cell cycle arrest, and impaired trophoblast proliferation","method":"Protein binding assay (TRIM38 identified as MEHP target protein), co-immunoprecipitation, ubiquitination assay, transcriptomic/proteomic analysis, cell cycle assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with functional rescue, single lab","pmids":["40059473"],"is_preprint":false},{"year":2025,"finding":"TRIM38 promotes K63-linked (non-degradative) ubiquitination of SQSTM1/p62 at K420, which disrupts the interaction between SQSTM1 and LC3 and impedes autophagic flux, thereby suppressing breast cancer progression","method":"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis (K420), LC3-SQSTM1 interaction assay, in vitro and in vivo tumor models","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — Co-IP with lysine mutagenesis and interaction disruption assay, single lab","pmids":["41347593"],"is_preprint":false},{"year":2025,"finding":"TRIM38 physically interacts with RIPK1 and promotes its ubiquitination and degradation, thereby suppressing NF-κB pathway activation in the context of diabetic nephropathy","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/rescue experiments in HK-2 cells, STZ-induced diabetic mouse model","journal":"Journal of physiology and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and western blotting rescue, single lab, single study","pmids":["42234342"],"is_preprint":false},{"year":2025,"finding":"TRIM38 interacts with HSPA5 (GRP78) and stabilizes it via K63-dependent ubiquitination, promoting M2 macrophage polarization and suppressing hepatic inflammation in metabolic liver disease","method":"Co-immunoprecipitation, ubiquitination assay, macrophage polarization assays, single-cell RNA sequencing, overexpression studies","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, single study","pmids":["40300357"],"is_preprint":false},{"year":2025,"finding":"The Brucella effector protein BspF crotonylates TRIM38 at K142, which promotes TRIM38-mediated K48-linked ubiquitination and degradation of TRAF6, thereby inhibiting NF-κB, p38 MAPK, and JNK signaling and reducing pro-inflammatory cytokine secretion to facilitate Brucella intracellular survival","method":"Crotonylation proteomics, site-specific mutagenesis (K142), ubiquitination assays, co-immunoprecipitation, cytokine measurement","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific PTM with mutagenesis and downstream ubiquitination assay, single lab","pmids":["40332097"],"is_preprint":false},{"year":2025,"finding":"TRIM38 inhibits the TAK1/JNK/P38 MAPK signaling pathway to protect against pressure overload-induced cardiac hypertrophy; Trim38 knockout activates TAK1 and JNK/P38, and dominant-negative TAK1 rescues Trim38 knockdown-induced cardiomyocyte hypertrophy","method":"Trim38 knockout mice with TAC model, adenoviral knockdown/overexpression in NRCMs, dominant-negative TAK1 rescue, ubiquitinomics analysis","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model, dominant-negative rescue, ubiquitinomics, single lab","pmids":["40314083"],"is_preprint":false},{"year":2025,"finding":"TRIM38 interacts with GRP78 (HSPA5) directly as shown by Co-IP, and upregulation of TRIM38 reduces endoplasmic reticulum stress marker proteins (GRP78, p-PERK, CHOP) to inhibit hepatic stellate cell activation","method":"Co-immunoprecipitation, western blotting, TRIM38 knockdown rescue experiments, CCl4 mouse liver fibrosis model","journal":"Biomedicines","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic detail in abstract","pmids":["42072369"],"is_preprint":false},{"year":2025,"finding":"RNF15 (an alias for TRIM38) binds ASK1 and conjugates K48-linked ubiquitination to ASK1, facilitating its degradation and inhibiting ASK1 downstream signaling; hepatocyte-specific Rnf15 ablation promotes steatohepatitis progression","method":"Hepatocyte-specific KO mice, lentivirus/AAV-mediated overexpression, co-immunoprecipitation, ubiquitination assay, NASH rodent models","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — hepatocyte-specific KO, AAV rescue, Co-IP, ubiquitination assay with multiple animal models, single lab but multiple orthogonal approaches","pmids":["41260394"],"is_preprint":false}],"current_model":"TRIM38 (also known as RNF15) is a cytoplasmic E3 ubiquitin ligase whose RING domain drives K48-linked polyubiquitination and proteasomal degradation of multiple immune signaling components—including TRIF (at K228), TRAF6, RIPK1, ASK1, MITA/STING, and viral proteins such as Zika NS3—while also mediating lysosome-dependent degradation of TAB2/3 independent of its ligase activity; through these substrate-directed mechanisms TRIM38 acts as a multifaceted negative regulator of TLR3/4-, TNFα/IL-1β-, RIG-I-, and TAK1-driven NF-κB and interferon signaling, and additionally performs K63-linked non-degradative ubiquitination (e.g., of HSPA5 and SQSTM1/p62) to modulate autophagy and macrophage polarization, with its activity subject to regulation by post-translational crotonylation (at K142 by the Brucella effector BspF) and by competition with TRIM25 for RIG-I binding."},"narrative":{"mechanistic_narrative":"TRIM38 (RNF15) is a cytoplasmic RING-domain E3 ubiquitin ligase that acts as a broad negative regulator of innate immune and inflammatory signaling by targeting pathway adaptors and kinases for degradation [PMID:21306652, PMID:26392463]. Through site-specific K48-linked polyubiquitination it drives proteasomal degradation of the TLR3/4 adaptor TRIF (at K228), engaging TRIF via its PRYSPRY domain while requiring an intact RING/B-box for catalysis [PMID:23056470, PMID:26392463]. The same degradative logic extends to additional signaling nodes: TRIM38 ubiquitinates and degrades TRAF6 to inactivate TAK1-dependent NF-κB and JNK/p38 MAPK signaling [PMID:39033726, PMID:40314083], degrades RIPK1 [PMID:42234342], and downregulates RIG-I by competing with TRIM25 for the RIG-I N-terminus and substituting activating K63 chains with degradative K48 chains as a negative-feedback brake on type I IFN [PMID:38630167]. In parallel, TRIM38 mediates lysosome-dependent degradation of TAB2/TAB3 independent of its ligase activity, suppressing TNFα- and IL-1β-triggered NF-κB activation, a route facilitated by the scaffold NLRP6 and operative in osteoclast/osteoblast differentiation [PMID:24434549, PMID:28295271, PMID:29753717]. TRIM38 also restrains antiviral and inflammatory programs by degrading MITA/STING and viral proteins such as Zika NS3 [PMID:38012139, PMID:40006954]. Beyond immune signaling, TRIM38 functions as a tumor and metabolic regulator: it degrades GLUT1, CCT6A, and p53, and performs non-degradative K63-linked ubiquitination of SQSTM1/p62 (at K420) to impede autophagic flux [PMID:34906161, PMID:40047371, PMID:40059473, PMID:41347593]. Its activity is itself tunable by post-translational modification, as the Brucella effector BspF crotonylates TRIM38 at K142 to enhance TRAF6 degradation and dampen host inflammation [PMID:40332097]. Hepatocyte-specific studies further establish TRIM38 as an ASK1-degrading suppressor of steatohepatitis [PMID:41260394].","teleology":[{"year":2011,"claim":"Established that TRIM38 is an enzymatically active cytoplasmic E3 ligase, defining the molecular activity that all later substrate work would build on.","evidence":"In vitro ubiquitination assays with RING-domain mutants and immunofluorescence localization","pmids":["21306652"],"confidence":"Medium","gaps":["No physiological substrate identified in this study","Linkage specificity not tied to a biological outcome"]},{"year":2012,"claim":"Identified the first physiological substrate, showing TRIM38 degrades the TLR3 adaptor TRIF and mapping the PRYSPRY-TRIF interaction, linking the ligase to innate immune attenuation.","evidence":"Co-IP with domain mapping, ubiquitination assays, MG132 rescue in reporter assays","pmids":["23056470"],"confidence":"Medium","gaps":["Ubiquitin chain topology and exact acceptor site not yet defined","In vivo relevance not tested"]},{"year":2014,"claim":"Revealed a ligase-independent mode of action, demonstrating TRIM38 routes TAB2/3 to lysosomal degradation to suppress TNFα/IL-1β-driven NF-κB, showing TRIM38 acts through two mechanistically distinct routes.","evidence":"Reciprocal Co-IP, knockout with NF-κB reporters, lysosome-inhibitor rescue and TAB2 translocation assays","pmids":["24434549"],"confidence":"High","gaps":["Adaptor delivering TAB2/3 to the lysosome not identified at this stage","How TRIM38 selects lysosomal vs proteasomal routing is unclear"]},{"year":2015,"claim":"Pinpointed the K228 acceptor site on TRIF and confirmed dual mechanisms in IFN-primed cells with knockout mice, cementing TRIM38 as an in vivo negative regulator of TLR signaling.","evidence":"Site-specific (K228) ubiquitination assays, proteasome rescue, Trim38 knockout mice challenged with polyI:C/LPS/Salmonella","pmids":["26392463"],"confidence":"High","gaps":["Structural basis of substrate selectivity not resolved","Relative contribution of proteasomal vs lysosomal arms in vivo not quantified"]},{"year":2017,"claim":"Showed that substrate engagement can be scaffold-assisted, with NLRP6 docking TAB2/3 to TRIM38 in synoviocytes, adding a regulatory layer to the lysosomal degradation route.","evidence":"Co-IP demonstrating three-way interaction and NF-κB assays in RA-FLS","pmids":["28295271"],"confidence":"Medium","gaps":["Direct vs indirect NLRP6-TRIM38 contact not resolved","Generality beyond synoviocytes untested"]},{"year":2018,"claim":"Extended the TAB2 degradation mechanism to bone biology, linking TRIM38-mediated NF-κB suppression to opposing effects on osteoclast and osteoblast differentiation.","evidence":"Gain/loss-of-function in bone precursors with NF-κB reporters and lysosome-dependent degradation assays","pmids":["29753717"],"confidence":"Medium","gaps":["In vivo skeletal phenotype of TRIM38 manipulation not established here","Direct ubiquitination of TAB2 not shown"]},{"year":2021,"claim":"Broadened the substrate repertoire beyond immunity by identifying GLUT1 as a degradation target, implicating TRIM38 in metabolic and tumor-suppressive control of glycolysis.","evidence":"TAP/MS substrate identification, Co-IP, ubiquitination assay, and bladder cancer xenografts","pmids":["34906161"],"confidence":"Medium","gaps":["Ubiquitin linkage type and acceptor lysine on GLUT1 not defined","Whether glycolysis effect is solely GLUT1-dependent unclear"]},{"year":2023,"claim":"Added CCT6A and MITA/STING as substrates, connecting TRIM38 to MYC-pathway control in colorectal cancer and to macrophage-polarization-dependent immune tolerance.","evidence":"Co-IP, site-specific ubiquitination (CCT6A K127/K138), AOM/DSS and macrophage polarization/pyroptosis models","pmids":["40047371","38012139"],"confidence":"Medium","gaps":["Context-dependence of substrate choice across tissues unresolved","Upstream signals directing TRIM38 to each substrate unknown"]},{"year":2024,"claim":"Defined a feedback mechanism on RIG-I in which TRIM38 competes with TRIM25 for the same N-terminal region and replaces activating K63 with degradative K48 ubiquitination, explaining IFN-I self-limitation.","evidence":"Co-IP with binding-region mapping (aa 25–43), ubiquitination and competition assays in an RSV infection model","pmids":["38630167"],"confidence":"Medium","gaps":["Stoichiometry of TRIM38/TRIM25 competition not quantified","Structural basis of mutually exclusive binding not determined"]},{"year":2024,"claim":"Directly demonstrated TRAF6 as a K48 ubiquitination substrate driving TAK1/NF-κB inactivation, providing the molecular basis for TRIM38's role in osteoclastogenesis.","evidence":"Co-IP, ubiquitination assay, TRAP/bone resorption assays and OVX mouse model","pmids":["39033726"],"confidence":"Medium","gaps":["TRAF6 acceptor lysines not mapped","Whether earlier TAK1/NF-κB phenotypes act solely via TRAF6 unresolved"]},{"year":2025,"claim":"Showed TRIM38 activity is itself regulated by a pathogen-driven PTM, with Brucella BspF crotonylating K142 to enhance TRAF6 degradation and suppress host inflammation.","evidence":"Crotonylation proteomics, K142 mutagenesis, ubiquitination assays and cytokine measurements","pmids":["40332097"],"confidence":"Medium","gaps":["Endogenous (non-pathogen) regulators of TRIM38 crotonylation unknown","Structural effect of K142 crotonylation on ligase activity undefined"]},{"year":2025,"claim":"Established TRIM38 as a degrader of ASK1 and p53 and a K63-modifier of SQSTM1/p62, expanding its reach to redox/stress signaling, cell-cycle control, and autophagy.","evidence":"Hepatocyte-specific Rnf15 KO with AAV rescue (ASK1), Co-IP/ubiquitination assays (p53, SQSTM1 K420), and tumor/NASH models","pmids":["41260394","40059473","41347593"],"confidence":"High","gaps":["How TRIM38 switches between K48-degradative and K63-non-degradative outputs is unresolved","Substrate-selection logic across these diverse targets unknown"]},{"year":2025,"claim":"Extended TRIM38 to viral restriction by degrading Zika NS3 through a lysosome-dependent, RING-dependent route while boosting RIG-I/MDA5-driven IFN-β.","evidence":"Co-IP, RING-deletion mutants, lysosome-inhibitor rescue and KO in U251 cells with IFN-β reporters","pmids":["40006954"],"confidence":"Medium","gaps":["Mechanism reconciling antiviral RIG-I upregulation with prior RIG-I degradation finding unclear","Direct ubiquitination of NS3 not topology-mapped"]},{"year":null,"claim":"It remains unresolved how a single ligase selects among its many substrates and switches between proteasomal K48, non-degradative K63, and ligase-independent lysosomal routing across such diverse tissue contexts.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","No unifying account of linkage/route selection","Endogenous physiological inputs that toggle TRIM38 activity largely undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3,1,2,7,12,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,9,12,14,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,9,14]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,11,12,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,12,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14]}],"complexes":[],"partners":["TRIF","TAB2","TAB3","TRAF6","RIG-I","TRIM25","RIPK1","ASK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00635","full_name":"E3 ubiquitin-protein ligase TRIM38","aliases":["RING finger protein 15","Tripartite motif-containing protein 38","Zinc finger protein RoRet"],"length_aa":465,"mass_kda":53.4,"function":"E3 ubiquitin-protein and E3 SUMO-protein ligase that acts as a regulator of innate immunity (PubMed:23056470). Acts as a negative regulator of type I interferon IFN-beta production by catalyzing 'Lys-48'-linked polyubiquitination of AZI2/NAP1, leading to its degradation (By similarity). Mediates 'Lys-48'-linked polyubiquitination and proteasomal degradation of the critical TLR adapter TICAM1, inhibiting TLR3-mediated type I interferon signaling (PubMed:23056470). Acts as positive regulator of the cGAS-STING pathway by acting as a E3 SUMO-protein ligase: mediates sumoylation of CGAS and STING, preventing their degradation and thereby activating the innate immune response to DNA virus (By similarity). Also acts as a negative regulator of NF-kappa-B signaling independently of its E3 protein ligase activity by promoting lysosome-dependent degradation of TAB2 and TAB3 adapters (PubMed:24434549)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O00635/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM38","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM38","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centrosome","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIM38"},"hgnc":{"alias_symbol":["RORET"],"prev_symbol":["RNF15"]},"alphafold":{"accession":"O00635","domains":[{"cath_id":"3.30.40.10","chopping":"2-88","consensus_level":"medium","plddt":83.5201,"start":2,"end":88},{"cath_id":"2.60.120.920","chopping":"278-460","consensus_level":"high","plddt":89.6997,"start":278,"end":460}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00635","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00635-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00635-F1-predicted_aligned_error_v6.png","plddt_mean":87.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM38","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM38"},"sequence":{"accession":"O00635","fasta_url":"https://rest.uniprot.org/uniprotkb/O00635.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00635/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00635"}},"corpus_meta":[{"pmid":"9288758","id":"PMC_9288758","title":"Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium.","date":"1997","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9288758","citation_count":1261,"is_preprint":false},{"pmid":"24434549","id":"PMC_24434549","title":"TRIM38 inhibits TNFα- and IL-1β-triggered NF-κB activation by mediating lysosome-dependent degradation of TAB2/3.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24434549","citation_count":125,"is_preprint":false},{"pmid":"28194022","id":"PMC_28194022","title":"Multifaceted roles of TRIM38 in innate immune and inflammatory responses.","date":"2017","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28194022","citation_count":88,"is_preprint":false},{"pmid":"26392463","id":"PMC_26392463","title":"TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26392463","citation_count":80,"is_preprint":false},{"pmid":"23056470","id":"PMC_23056470","title":"TRIM38 negatively regulates TLR3-mediated IFN-β signaling by targeting TRIF for degradation.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23056470","citation_count":67,"is_preprint":false},{"pmid":"29753717","id":"PMC_29753717","title":"TRIM38 regulates NF-κB activation through TAB2 degradation in osteoclast and osteoblast differentiation.","date":"2018","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/29753717","citation_count":42,"is_preprint":false},{"pmid":"34906161","id":"PMC_34906161","title":"TRIM38 triggers the uniquitination and degradation of glucose transporter type 1 (GLUT1) to restrict tumor progression in bladder cancer.","date":"2021","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34906161","citation_count":33,"is_preprint":false},{"pmid":"28295271","id":"PMC_28295271","title":"NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes.","date":"2017","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/28295271","citation_count":33,"is_preprint":false},{"pmid":"21306652","id":"PMC_21306652","title":"Enterovirus 71 induces degradation of TRIM38, a potential E3 ubiquitin ligase.","date":"2011","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/21306652","citation_count":17,"is_preprint":false},{"pmid":"34426118","id":"PMC_34426118","title":"TRIM38 protects chondrocytes from IL-1β-induced apoptosis and degeneration via negatively modulating nuclear factor (NF)-κB signaling.","date":"2021","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34426118","citation_count":13,"is_preprint":false},{"pmid":"37566200","id":"PMC_37566200","title":"TRIM38 suppresses migration, invasion, metastasis, and proliferation in non-small cell lung cancer (NSCLC) via regulating the AMPK/NF-κB/NLRP3 pathway.","date":"2023","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37566200","citation_count":12,"is_preprint":false},{"pmid":"36061751","id":"PMC_36061751","title":"TRIM38 protects H9c2 cells from hypoxia/reoxygenation injury via the TRAF6/TAK1/NF-κB signalling pathway.","date":"2022","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/36061751","citation_count":10,"is_preprint":false},{"pmid":"40047371","id":"PMC_40047371","title":"TRIM38 Suppresses the Progression of Colorectal Cancer via Enhancing CCT6A Ubiquitination to Inhibit the MYC Pathway.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40047371","citation_count":8,"is_preprint":false},{"pmid":"38012139","id":"PMC_38012139","title":"Investigation into the role of the MITA-TRIM38 interaction in regulating pyroptosis and maintaining immune tolerance at the maternal-fetal interface.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38012139","citation_count":8,"is_preprint":false},{"pmid":"38630167","id":"PMC_38630167","title":"TRIM38 Induced in Respiratory Syncytial Virus-infected Cells Downregulates Type I Interferon Expression by Competing with TRIM25 to Bind RIG-I.","date":"2024","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/38630167","citation_count":7,"is_preprint":false},{"pmid":"10978534","id":"PMC_10978534","title":"BSPRY, a novel protein of the Ro-Ret family.","date":"2000","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10978534","citation_count":6,"is_preprint":false},{"pmid":"40006954","id":"PMC_40006954","title":"TRIM38 Inhibits Zika Virus by Upregulating RIG-I/MDA5 Pathway and Promoting Ubiquitin-Mediated Degradation of Viral NS3 Protein.","date":"2025","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/40006954","citation_count":5,"is_preprint":false},{"pmid":"40332097","id":"PMC_40332097","title":"The Brucella Effector Protein BspF Crotonylates TRIM38 to Inhibit NF-κB and MAPK Signaling Pathway.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40332097","citation_count":5,"is_preprint":false},{"pmid":"21789858","id":"PMC_21789858","title":"[Identification A novel protein TRIM38 that activate NF-kappaB signaling pathways].","date":"2011","source":"Zhonghua shi yan he lin chuang bing du xue za zhi = Zhonghua shiyan he linchuang bingduxue zazhi = Chinese journal of experimental and clinical virology","url":"https://pubmed.ncbi.nlm.nih.gov/21789858","citation_count":5,"is_preprint":false},{"pmid":"40300357","id":"PMC_40300357","title":"E3 ubiquitin ligase TRIM38 regulates macrophage polarization to reduce hepatic inflammation by interacting with HSPA5.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40300357","citation_count":4,"is_preprint":false},{"pmid":"40059473","id":"PMC_40059473","title":"Di-(2-ethylhexyl)-phthalate disrupts mouse placental growth by regulating the cell cycle of mouse placental trophoblasts through the Trim38-p53 signaling axis.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40059473","citation_count":4,"is_preprint":false},{"pmid":"40314083","id":"PMC_40314083","title":"Trim38 attenuates pressure overload‑induced cardiac hypertrophy by suppressing the TAK1/JNK/P38 signaling pathway.","date":"2025","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40314083","citation_count":3,"is_preprint":false},{"pmid":"39033726","id":"PMC_39033726","title":"Active fraction of Polyrhachis vicina (Rogers) inhibits osteoclastogenesis by targeting Trim38 mediated proteasomal degradation of TRAF6.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39033726","citation_count":3,"is_preprint":false},{"pmid":"40362389","id":"PMC_40362389","title":"Characterization and Functional Analysis of Trim38 in the Immune Response of the Large Yellow Croaker (Larimichthys crocea) Against Pseudomonas plecoglossicida Infection.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40362389","citation_count":3,"is_preprint":false},{"pmid":"41476316","id":"PMC_41476316","title":"Tetrahydromagnolol targets TRIM38 to mediate PANoptosis in cancer cells and has the potential for synergistic cancer therapy.","date":"2025","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41476316","citation_count":2,"is_preprint":false},{"pmid":"41347593","id":"PMC_41347593","title":"TRIM38 Suppresses Breast Cancer Progression via Modulating SQSTM1 Ubiquitination and Autophagic Flux.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41347593","citation_count":1,"is_preprint":false},{"pmid":"42072369","id":"PMC_42072369","title":"α-Hederin Alleviates Endoplasmic Reticulum Stress by Upregulating TRIM38 Expression, Thereby Inhibiting Hepatic Stellate Cell Activation and Liver Fibrosis.","date":"2026","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/42072369","citation_count":0,"is_preprint":false},{"pmid":"42234342","id":"PMC_42234342","title":"TRIM38 alleviates the pathogenesis of diabetic nephropathy by suppressing NF-κB activation via inducing RIPK1 degradation.","date":"2026","source":"Journal of physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42234342","citation_count":0,"is_preprint":false},{"pmid":"41260394","id":"PMC_41260394","title":"Metabolic insults-initialised nonalcoholic steatohepatitis promoted by fine particulate matter challenge: A mechanism involving RNF15-driven ASK1 degradation.","date":"2025","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41260394","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16530,"output_tokens":5024,"usd":0.062475,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13277,"output_tokens":4506,"usd":0.089517,"stage2_stop_reason":"end_turn"},"total_usd":0.151992,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM38 constitutively interacts with TAB2 and TAB3 and promotes their lysosome-dependent degradation independent of its E3 ubiquitin ligase activity, thereby negatively regulating TNFα- and IL-1β-triggered NF-κB activation\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown/knockout with NF-κB reporter assays, lysosome inhibitor rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KO with defined phenotype, lysosome-dependent mechanism confirmed by multiple orthogonal approaches including TAB2 translocation assay\",\n      \"pmids\": [\"24434549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM38 catalyzes K48-linked polyubiquitination of the TLR3/4 adaptor TRIF at K228 and promotes its proteasomal degradation, negatively regulating TLR3/4-mediated type I IFN and proinflammatory cytokine induction; additionally, TRIM38 induced by type I IFNs mediates lysosomal degradation of TAB2 to suppress TNFα/IL-1β signaling in IFN-primed immune cells\",\n      \"method\": \"Ubiquitination assays with site-specific mutagenesis (K228), proteasome inhibitor rescue, Trim38 knockout mice challenged with polyI:C/LPS/Salmonella\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination assay with mutagenesis, KO mouse model with in vivo phenotype, two orthogonal mechanisms demonstrated\",\n      \"pmids\": [\"26392463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM38 targets the TLR3 adaptor TRIF for K48-linked polyubiquitination and proteasomal degradation; the PRYSPRY domain of TRIM38 interacts with the N-terminus of TRIF, and the RING/B-box domain is required for ubiquitination activity\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, ubiquitination assays, MG132 rescue, overexpression/knockdown reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and ubiquitination assay in single lab, consistent with independent replication in PMID:26392463\",\n      \"pmids\": [\"23056470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM38 functions as an E3 ubiquitin ligase, promoting both K48- and K63-linked polyubiquitination of cellular proteins and self-ubiquitination; an intact RING domain is required for these activities; TRIM38 localizes to the cytoplasm; enterovirus 71 infection induces TRIM38 degradation\",\n      \"method\": \"Ubiquitination assays with RING domain mutants, immunofluorescence localization, viral infection experiments\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro ubiquitination assay with domain mutagenesis, direct localization by immunofluorescence, single lab\",\n      \"pmids\": [\"21306652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes, acting as a docking scaffold to promote TAB2/3 lysosomal degradation and suppress NF-κB activation\",\n      \"method\": \"Co-immunoprecipitation, overexpression studies in RA-FLS, NF-κB activity assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP demonstrating three-way interaction, single lab, consistent with prior TRIM38-TAB2/3 mechanism\",\n      \"pmids\": [\"28295271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM38 promotes lysosome-dependent degradation of TAB2 in osteoclast precursor cells, suppressing RANKL-induced NF-κB activation and inhibiting osteoclast differentiation; conversely, TRIM38 promotes osteoblast differentiation via NF-κB suppression\",\n      \"method\": \"Overexpression/knockdown in osteoclast and osteoblast precursors, NF-κB reporter assays, lysosome-dependent degradation assays\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined cellular phenotype, mechanistic link to TAB2 degradation, single lab\",\n      \"pmids\": [\"29753717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM38 interacts with GLUT1 and promotes its ubiquitination and degradation, thereby restricting glycolytic capacity and tumor progression in bladder cancer cells\",\n      \"method\": \"TAP/MS substrate identification, co-immunoprecipitation, ubiquitination assay, loss-of-function proliferation/migration assays, xenograft model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based substrate identification followed by Co-IP and functional rescue, single lab\",\n      \"pmids\": [\"34906161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM38 binds CCT6A and promotes its K48-linked ubiquitination and degradation at K127/K138 residues; loss of CCT6A degradation elevates c-Myc protein levels and activates the MYC pathway in colorectal cancer\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis, KO/KD functional assays, AOM/DSS tumorigenesis model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ubiquitination with lysine mutagenesis, Co-IP, in vivo model, single lab\",\n      \"pmids\": [\"40047371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM38 mediates K48-linked ubiquitination of MITA (STING) promoting its degradation; this ubiquitination is higher in M2 macrophages, keeping MITA expression low and inhibiting pyroptosis, thereby maintaining immune tolerance at the maternal-fetal interface\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, macrophage polarization experiments (M1/M2), functional pyroptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitination assay, mechanistic link to pyroptosis in defined cell context, single lab\",\n      \"pmids\": [\"38012139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM38, induced by IFN-I during RSV infection, downregulates RIG-I by K48-linked ubiquitination and promotes RIG-I degradation; TRIM38 competes with TRIM25 for binding to the RIG-I N-terminus (aa 25–43 region), preventing TRIM25-mediated K63 ubiquitination and activation of RIG-I, thereby attenuating IFN-I production as a negative feedback mechanism\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, ubiquitination assays, overexpression competition experiments, RSV infection model\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with defined binding region mapping, ubiquitination assay, competition experiment, single lab\",\n      \"pmids\": [\"38630167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 interacts with Zika virus NS3 protein via its RING domain and promotes NS3 degradation through a lysosome-dependent mechanism utilizing its E3 ligase activity; RING domain deletion abrogates NS3 interaction and impairs antiviral activity; TRIM38 also upregulates the RIG-I/MDA5 pathway and IFN-β early during ZIKV infection\",\n      \"method\": \"Co-immunoprecipitation, RING domain deletion mutants, lysosome inhibitor rescue, overexpression/knockout in U251 cells, IFN-β reporter assays\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mutants and lysosome inhibitor rescue, KO confirmed with opposite phenotype, single lab\",\n      \"pmids\": [\"40006954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM38 promotes TRAF6 degradation, leading to inactivation of the TAK1/NF-κB signaling pathway and protection of H9c2 cardiomyoblasts from hypoxia/reoxygenation injury; TAK1 inhibition rescues the H/R injury exacerbated by TRIM38 deficiency\",\n      \"method\": \"Adenoviral overexpression/knockdown, western blotting, TAK1 inhibitor (5Z-7-oxozeaenol) rescue experiments\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological rescue and western blotting only; TRAF6 ubiquitination not directly demonstrated in this paper\",\n      \"pmids\": [\"36061751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM38 mediates K48-linked polyubiquitination of TRAF6 and promotes its proteasomal degradation in response to RANKL, thereby inhibiting NFATc1 activity and osteoclastogenesis; TRIM38 binds TRAF6 directly\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown of TRIM38, TRAP staining, bone resorption assay, OVX mouse model\",\n      \"journal\": \"Phytomedicine : international journal of phytotherapy and phytopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and in vivo rescue model, single lab\",\n      \"pmids\": [\"39033726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 binds p53 and promotes its ubiquitination-proteasomal degradation; MEHP (a DEHP metabolite) inhibits TRIM38-mediated ubiquitination of p53, leading to p53 accumulation, cell cycle arrest, and impaired trophoblast proliferation\",\n      \"method\": \"Protein binding assay (TRIM38 identified as MEHP target protein), co-immunoprecipitation, ubiquitination assay, transcriptomic/proteomic analysis, cell cycle assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with functional rescue, single lab\",\n      \"pmids\": [\"40059473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 promotes K63-linked (non-degradative) ubiquitination of SQSTM1/p62 at K420, which disrupts the interaction between SQSTM1 and LC3 and impedes autophagic flux, thereby suppressing breast cancer progression\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis (K420), LC3-SQSTM1 interaction assay, in vitro and in vivo tumor models\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Co-IP with lysine mutagenesis and interaction disruption assay, single lab\",\n      \"pmids\": [\"41347593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 physically interacts with RIPK1 and promotes its ubiquitination and degradation, thereby suppressing NF-κB pathway activation in the context of diabetic nephropathy\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/rescue experiments in HK-2 cells, STZ-induced diabetic mouse model\",\n      \"journal\": \"Journal of physiology and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and western blotting rescue, single lab, single study\",\n      \"pmids\": [\"42234342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 interacts with HSPA5 (GRP78) and stabilizes it via K63-dependent ubiquitination, promoting M2 macrophage polarization and suppressing hepatic inflammation in metabolic liver disease\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, macrophage polarization assays, single-cell RNA sequencing, overexpression studies\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, single study\",\n      \"pmids\": [\"40300357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The Brucella effector protein BspF crotonylates TRIM38 at K142, which promotes TRIM38-mediated K48-linked ubiquitination and degradation of TRAF6, thereby inhibiting NF-κB, p38 MAPK, and JNK signaling and reducing pro-inflammatory cytokine secretion to facilitate Brucella intracellular survival\",\n      \"method\": \"Crotonylation proteomics, site-specific mutagenesis (K142), ubiquitination assays, co-immunoprecipitation, cytokine measurement\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific PTM with mutagenesis and downstream ubiquitination assay, single lab\",\n      \"pmids\": [\"40332097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 inhibits the TAK1/JNK/P38 MAPK signaling pathway to protect against pressure overload-induced cardiac hypertrophy; Trim38 knockout activates TAK1 and JNK/P38, and dominant-negative TAK1 rescues Trim38 knockdown-induced cardiomyocyte hypertrophy\",\n      \"method\": \"Trim38 knockout mice with TAC model, adenoviral knockdown/overexpression in NRCMs, dominant-negative TAK1 rescue, ubiquitinomics analysis\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model, dominant-negative rescue, ubiquitinomics, single lab\",\n      \"pmids\": [\"40314083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 interacts with GRP78 (HSPA5) directly as shown by Co-IP, and upregulation of TRIM38 reduces endoplasmic reticulum stress marker proteins (GRP78, p-PERK, CHOP) to inhibit hepatic stellate cell activation\",\n      \"method\": \"Co-immunoprecipitation, western blotting, TRIM38 knockdown rescue experiments, CCl4 mouse liver fibrosis model\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"42072369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF15 (an alias for TRIM38) binds ASK1 and conjugates K48-linked ubiquitination to ASK1, facilitating its degradation and inhibiting ASK1 downstream signaling; hepatocyte-specific Rnf15 ablation promotes steatohepatitis progression\",\n      \"method\": \"Hepatocyte-specific KO mice, lentivirus/AAV-mediated overexpression, co-immunoprecipitation, ubiquitination assay, NASH rodent models\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — hepatocyte-specific KO, AAV rescue, Co-IP, ubiquitination assay with multiple animal models, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"41260394\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM38 (also known as RNF15) is a cytoplasmic E3 ubiquitin ligase whose RING domain drives K48-linked polyubiquitination and proteasomal degradation of multiple immune signaling components—including TRIF (at K228), TRAF6, RIPK1, ASK1, MITA/STING, and viral proteins such as Zika NS3—while also mediating lysosome-dependent degradation of TAB2/3 independent of its ligase activity; through these substrate-directed mechanisms TRIM38 acts as a multifaceted negative regulator of TLR3/4-, TNFα/IL-1β-, RIG-I-, and TAK1-driven NF-κB and interferon signaling, and additionally performs K63-linked non-degradative ubiquitination (e.g., of HSPA5 and SQSTM1/p62) to modulate autophagy and macrophage polarization, with its activity subject to regulation by post-translational crotonylation (at K142 by the Brucella effector BspF) and by competition with TRIM25 for RIG-I binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM38 (RNF15) is a cytoplasmic RING-domain E3 ubiquitin ligase that acts as a broad negative regulator of innate immune and inflammatory signaling by targeting pathway adaptors and kinases for degradation [#3, #1]. Through site-specific K48-linked polyubiquitination it drives proteasomal degradation of the TLR3/4 adaptor TRIF (at K228), engaging TRIF via its PRYSPRY domain while requiring an intact RING/B-box for catalysis [#2, #1]. The same degradative logic extends to additional signaling nodes: TRIM38 ubiquitinates and degrades TRAF6 to inactivate TAK1-dependent NF-\\u03baB and JNK/p38 MAPK signaling [#12, #18], degrades RIPK1 [#15], and downregulates RIG-I by competing with TRIM25 for the RIG-I N-terminus and substituting activating K63 chains with degradative K48 chains as a negative-feedback brake on type I IFN [#9]. In parallel, TRIM38 mediates lysosome-dependent degradation of TAB2/TAB3 independent of its ligase activity, suppressing TNF\\u03b1- and IL-1\\u03b2-triggered NF-\\u03baB activation, a route facilitated by the scaffold NLRP6 and operative in osteoclast/osteoblast differentiation [#0, #4, #5]. TRIM38 also restrains antiviral and inflammatory programs by degrading MITA/STING and viral proteins such as Zika NS3 [#8, #10]. Beyond immune signaling, TRIM38 functions as a tumor and metabolic regulator: it degrades GLUT1, CCT6A, and p53, and performs non-degradative K63-linked ubiquitination of SQSTM1/p62 (at K420) to impede autophagic flux [#6, #7, #13, #14]. Its activity is itself tunable by post-translational modification, as the Brucella effector BspF crotonylates TRIM38 at K142 to enhance TRAF6 degradation and dampen host inflammation [#17]. Hepatocyte-specific studies further establish TRIM38 as an ASK1-degrading suppressor of steatohepatitis [#20].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that TRIM38 is an enzymatically active cytoplasmic E3 ligase, defining the molecular activity that all later substrate work would build on.\",\n      \"evidence\": \"In vitro ubiquitination assays with RING-domain mutants and immunofluorescence localization\",\n      \"pmids\": [\"21306652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No physiological substrate identified in this study\", \"Linkage specificity not tied to a biological outcome\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the first physiological substrate, showing TRIM38 degrades the TLR3 adaptor TRIF and mapping the PRYSPRY-TRIF interaction, linking the ligase to innate immune attenuation.\",\n      \"evidence\": \"Co-IP with domain mapping, ubiquitination assays, MG132 rescue in reporter assays\",\n      \"pmids\": [\"23056470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain topology and exact acceptor site not yet defined\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a ligase-independent mode of action, demonstrating TRIM38 routes TAB2/3 to lysosomal degradation to suppress TNF\\u03b1/IL-1\\u03b2-driven NF-\\u03baB, showing TRIM38 acts through two mechanistically distinct routes.\",\n      \"evidence\": \"Reciprocal Co-IP, knockout with NF-\\u03baB reporters, lysosome-inhibitor rescue and TAB2 translocation assays\",\n      \"pmids\": [\"24434549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor delivering TAB2/3 to the lysosome not identified at this stage\", \"How TRIM38 selects lysosomal vs proteasomal routing is unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Pinpointed the K228 acceptor site on TRIF and confirmed dual mechanisms in IFN-primed cells with knockout mice, cementing TRIM38 as an in vivo negative regulator of TLR signaling.\",\n      \"evidence\": \"Site-specific (K228) ubiquitination assays, proteasome rescue, Trim38 knockout mice challenged with polyI:C/LPS/Salmonella\",\n      \"pmids\": [\"26392463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of substrate selectivity not resolved\", \"Relative contribution of proteasomal vs lysosomal arms in vivo not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that substrate engagement can be scaffold-assisted, with NLRP6 docking TAB2/3 to TRIM38 in synoviocytes, adding a regulatory layer to the lysosomal degradation route.\",\n      \"evidence\": \"Co-IP demonstrating three-way interaction and NF-\\u03baB assays in RA-FLS\",\n      \"pmids\": [\"28295271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect NLRP6-TRIM38 contact not resolved\", \"Generality beyond synoviocytes untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the TAB2 degradation mechanism to bone biology, linking TRIM38-mediated NF-\\u03baB suppression to opposing effects on osteoclast and osteoblast differentiation.\",\n      \"evidence\": \"Gain/loss-of-function in bone precursors with NF-\\u03baB reporters and lysosome-dependent degradation assays\",\n      \"pmids\": [\"29753717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo skeletal phenotype of TRIM38 manipulation not established here\", \"Direct ubiquitination of TAB2 not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened the substrate repertoire beyond immunity by identifying GLUT1 as a degradation target, implicating TRIM38 in metabolic and tumor-suppressive control of glycolysis.\",\n      \"evidence\": \"TAP/MS substrate identification, Co-IP, ubiquitination assay, and bladder cancer xenografts\",\n      \"pmids\": [\"34906161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type and acceptor lysine on GLUT1 not defined\", \"Whether glycolysis effect is solely GLUT1-dependent unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added CCT6A and MITA/STING as substrates, connecting TRIM38 to MYC-pathway control in colorectal cancer and to macrophage-polarization-dependent immune tolerance.\",\n      \"evidence\": \"Co-IP, site-specific ubiquitination (CCT6A K127/K138), AOM/DSS and macrophage polarization/pyroptosis models\",\n      \"pmids\": [\"40047371\", \"38012139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependence of substrate choice across tissues unresolved\", \"Upstream signals directing TRIM38 to each substrate unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a feedback mechanism on RIG-I in which TRIM38 competes with TRIM25 for the same N-terminal region and replaces activating K63 with degradative K48 ubiquitination, explaining IFN-I self-limitation.\",\n      \"evidence\": \"Co-IP with binding-region mapping (aa 25\\u201343), ubiquitination and competition assays in an RSV infection model\",\n      \"pmids\": [\"38630167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of TRIM38/TRIM25 competition not quantified\", \"Structural basis of mutually exclusive binding not determined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Directly demonstrated TRAF6 as a K48 ubiquitination substrate driving TAK1/NF-\\u03baB inactivation, providing the molecular basis for TRIM38's role in osteoclastogenesis.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, TRAP/bone resorption assays and OVX mouse model\",\n      \"pmids\": [\"39033726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRAF6 acceptor lysines not mapped\", \"Whether earlier TAK1/NF-\\u03baB phenotypes act solely via TRAF6 unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed TRIM38 activity is itself regulated by a pathogen-driven PTM, with Brucella BspF crotonylating K142 to enhance TRAF6 degradation and suppress host inflammation.\",\n      \"evidence\": \"Crotonylation proteomics, K142 mutagenesis, ubiquitination assays and cytokine measurements\",\n      \"pmids\": [\"40332097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous (non-pathogen) regulators of TRIM38 crotonylation unknown\", \"Structural effect of K142 crotonylation on ligase activity undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established TRIM38 as a degrader of ASK1 and p53 and a K63-modifier of SQSTM1/p62, expanding its reach to redox/stress signaling, cell-cycle control, and autophagy.\",\n      \"evidence\": \"Hepatocyte-specific Rnf15 KO with AAV rescue (ASK1), Co-IP/ubiquitination assays (p53, SQSTM1 K420), and tumor/NASH models\",\n      \"pmids\": [\"41260394\", \"40059473\", \"41347593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIM38 switches between K48-degradative and K63-non-degradative outputs is unresolved\", \"Substrate-selection logic across these diverse targets unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended TRIM38 to viral restriction by degrading Zika NS3 through a lysosome-dependent, RING-dependent route while boosting RIG-I/MDA5-driven IFN-\\u03b2.\",\n      \"evidence\": \"Co-IP, RING-deletion mutants, lysosome-inhibitor rescue and KO in U251 cells with IFN-\\u03b2 reporters\",\n      \"pmids\": [\"40006954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism reconciling antiviral RIG-I upregulation with prior RIG-I degradation finding unclear\", \"Direct ubiquitination of NS3 not topology-mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single ligase selects among its many substrates and switches between proteasomal K48, non-degradative K63, and ligase-independent lysosomal routing across such diverse tissue contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"No unifying account of linkage/route selection\", \"Endogenous physiological inputs that toggle TRIM38 activity largely undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3, 1, 2, 7, 12, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 9, 12, 14, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 9, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 11, 12, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 12, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRIF\", \"TAB2\", \"TAB3\", \"TRAF6\", \"RIG-I\", \"TRIM25\", \"RIPK1\", \"ASK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}